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Abstract Introduction IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear. Methods In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2R172K transgenic mice. Results We found that thrombopoietin (TPO)‐overexpressed Idh2R172K (Idh2R172K + TPO) mice had accelerated progression to MF, compared with TPO‐overexpressed Idh2‐wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single‐cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2R172K + TPO group. Furthermore, Idh2R172K mice at age of 18 months had larger spleens, increased S100a8/a9‐Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations. Conclusion Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2R172K + TPO mice.

Abstract The European Leukemia Net recommendations provide valuable guidance in treatment decisions of patients with acute myeloid leukemia (AML). However, the genetic complexity and heterogeneity of AML are not fully covered, notwithstanding that gene expression analysis is crucial in the risk stratification of AML. The Stellae-123 score, an AI-based model that captures gene expression patterns, has demonstrated robust survival predictions in AML patients across four western-population cohorts. This study aims to evaluate the applicability of Stellae-123 in a Taiwanese cohort. The Stellae-123 model was applied to 304 de novo AML patients diagnosed and treated at the National Taiwan University Hospital. We find that the pretrained (BeatAML-based) model achieved c-indexes of 0.631 and 0.632 for the prediction of overall survival (OS) and relapse-free survival (RFS), respectively. Model retraining within our cohort further improve the cross-validated c-indexes to 0.667 and 0.667 for OS and RFS prediction, respectively. Multivariable analysis identify both pretrained and retrained models as independent prognostic biomarkers. We further show that incorporating age, Stellae-123, and ELN classification remarkably improves risk stratification, revealing c-indices of 0.73 and 0.728 for OS and RFS, respectively. In summary, the Stellae-123 gene expression signature is a valuable prognostic tool for AML patients and model retraining can improve the accuracy and applicability of the model in different populations.

Background/purpose: The S100 family proteins are involved in a variety of important biological processes, most notably immune and inflammatory responses. Their dysregulation also plays a role in the pathogenesis of human cancers. S100A4, also known as metastasin, has long been regarded as a biological marker in tumor progression and metastasis in multiple solid cancers, but its clinical significance in acute myeloid leukemia (AML) has not been extensively studied. Methods: We retrospectively studied the association between S100A4 gene expression and the clinical characteristics, mutational and transcriptomic profiles of 227 AML patients treated with standard intensive chemotherapy. Genetic mutations of myeloid disease associated genes were analyzed by Sanger sequencing. Microarray-based transcriptomic gene expression profiling was performed on archived bone marrow mononuclear cells. Bioinformatic analyses, including differential gene expression and gene set enrichment analysis, were conducted to delineate the underlying pathogenic mechanisms. Results: Higher S100A4 expression was associated with older age, monocytic differentiation of leukemic cells, and adverse clinical outcome. S100A4 high-expressors had inferior overall survival and disease-free survival; this finding could be validated in the TCGA AML cohort (both the microarray and RNA-seq platforms). Multivariate Cox regression analysis supported S100A4 as an independent prognostic factor. Bioinformatic analysis showed that AML with higher S100A4 expression was enriched for the interferon, NLRP3 inflammasome, and epithelial–mesenchymal transition pathways. Conclusion: This study provides evidence that S100A4 overexpression serves as a poor prognostic biomarker in AML, holds potential to guide treatment planning in the clinic, and indicates novel therapeutic directions.

Abstract RUNX1 mutations are frequently detected in various myeloid neoplasms and implicate unfavourable clinical outcomes in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). On the other hand, high expression of RUNX1 is also correlated with poor prognosis in AML patients. However, the clinical relevancy of RUNX1 expression in MDS patients remains elusive. This study aimed to investigate the prognostic and biologic impacts of RUNX1 expression in MDS patients. We recruited 341 MDS patients who had sufficient bone marrow samples for next‐generation sequencing. Higher RUNX1 expression occurred more frequently in the patients with Revised International Prognostic Scoring System (IPSS‐R) higher‐risk MDS than the lower‐risk group. It was closely associated with poor‐risk cytogenetics and mutations in ASXL1, NPM1, RUNX1, SRSF2, STAG2, TET2 and TP53. Furthermore, patients with higher RUNX1 expression had significantly shorter leukaemia‐free survival (LFS) and overall survival (OS) than those with lower expression. Subgroups analysis revealed that higher‐RUNX1 group consistently had shorter LFS and OS than the lower‐RUNX1 group, no matter RUNX1 was mutated or not. The same findings were observed in IPSS‐R subgroups. In multivariable analysis, higher RUNX1 expression appeared as an independent adverse risk factor for survival. The prognostic significance of RUNX1 expression was validated in two external public cohorts, GSE 114922 and GSE15061. In summary, we present the characteristics and prognosis of MDS patients with various RUNX1 expressions and propose that RUNX1 expression complement RUNX1 mutation in MDS prognostication, wherein patients with wild RUNX1 but high expression may need more proactive treatment.

Abstract Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization.

Abstract Background Allogeneic stem cell transplantation (allo‐HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL). Aim This study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)‐based or total body irradiation (TBI)‐based regimen in a Chinese population. Methods We enrolled 224 adult patients with ALL who received allo‐HSCT at National Taiwan University Hospital between 1997 and 2016. Results The median age at transplantation was 33 years. Before allo‐HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy‐based conditioning, either myeloablative (MA) or reduced‐intensity stem cell transplantation (RIST), and 83 patients received a TBI‐based regimen (MA‐TBI). Patients receiving the MA‐Bu regimen had longer relapse‐free survival (RFS) than those receiving the MA‐TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment‐related mortality (TRM), or incidences of grade 3–4 acute graft‐versus‐host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA‐Bu and MA‐TBI groups regarding the incidence of grade 3–4 acute GvHD, grade 2–4, and all‐grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo‐HSCT was the only risk factor impacting RFS and OS. Conclusion In summary, patients receiving Bu/Cy‐based or TBI‐based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu‐based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long‐term outcomes.

This study demonstrates a novel cell manipulation microdevice for cell docking, culturing, cell-cell contact and interaction by microfluidic manipulation of heterogeneous cell suspensions. Heterogeneous cell suspensions include disparate blood cells of natural killer cells and leukemia cancer cells for immune cell transplantation therapy. However, NK cell alloreactivity from different healthy donors present various recovery response levels. Little is still known about the interactions and cytotoxicity effects between donor NK cells and recipient cancer cells. The cell-based micro device first showed the capability of cell docking, movement, contact and cell-cell interaction with respect to cell cytotoxicity of NK cells against cancer cells. With various flow tests for live cell loading, flow rates of 10 μL/h were chosen for injection in the central and side flows such that both types of suspension cells could be gently docked at the gap structure in a reaction zone. The trapping number of particles and cells was linearly proportional to the gap length. Finally, the cytotoxicity of around 40% was found to be similar in the case of dilute cells and a large cell population. As a result, the cell manipulation microdevice has been validated for live suspensions of natural killer and cancer cells, and exhibited the capability to measure the cytotoxicity of dilute cell suspensions.